Efficient binding to and entry into host cells is a crucial step for many pathogens to establish infection. Epstein–Barr virus (EBV) predominantly infects human B cells and epithelial cells by fusion of the viral envelope with the host cell membrane. Although the mechanism of entry into B cells has been well documented, the mechanism for entry into epithelial cells has remained elusive. Now, in two studies, Zhang, Li, Wang et al. and Chen et al. identify ephrin type-A receptor 2 (EPHA2) as an EBV epithelial cell receptor. CRISPR–Cas9-mediated knockout markedly reduced fusion and infection of epithelial cells with EBV, whereas overexpression of the receptor increased fusion and infection, suggesting that EPHA2 is important for EBV infection of epithelial cells. In agreement with this, antibodies against EPHA2, an EPHA2 ligand and an EPHA2 inhibitor all efficiently blocked EBV epithelial cell infection. The authors were also able to show that the EBV entry glycoproteins gH–gL and gB are involved in binding to EPHA2. In another study, Swidergall et al. show that EPHA2 functions as a non-classical pattern-recognition receptor in oral epithelial cells to sense the presence of high levels of β-glucans on the surface of Candida albicans. They showed that EPHA2 interacts directly with β-glucans from C. albicans as well as from other fungi, including Aspergillus fumigatus. Activation of EPHA2 not only contributes to receptor-induced endocytosis of C. albicans but also leads to the activation of signalling pathways in oral epithelial cells and the production of pro-inflammatory cytokines and defence peptides. Finally, Aaron, Jamklang et al. reported that the EPHA2 signalling pathway promotes the migration of the fungal pathogen Cryptococcus neoformans across the blood–brain barrier. The authors report that C. neoformans activates EPHA2 in brain endothelial cells, which enhances the transcellular migration of the fungus across brain endothelial cells in an in vitro model of the blood–brain barrier, which may be dependent on CD44.